PROJECT SUMMARY The proposed research will determine whether acute administration of the dopamine precursor levodopa will reverse the impact of inflammation on functional connectivity within reward circuitry as well as anhedonia and psychomotor retardation in patients with major depressive disorder (MDD). Biomarkers of inflammation, such as inflammatory cytokines and acute-phase proteins like C-reactive protein (CRP), are reliably elevated in a significant proportion of patients with mood disorders. Furthermore, administration of cytokines or cytokine inducers to laboratory animals and humans is associated with depressive symptoms including anhedonia, a core symptom of depression that reflects impaired reward processing. Previous neuroimaging findings demonstrate that inflammatory cytokines produce behavioral changes in part through effects on striatal dopamine. For example, inflammatory stimuli have been shown to decrease neural activation of the ventral striatum to hedonic reward and to decrease striatal dopamine release in association with reduced effort-based motivation for reward. Moreover, our recently published data in patients with MDD have demonstrated a relationship between increased inflammation (as measured by plasma CRP and inflammatory cytokines) and decreased functional connectivity within ventral and dorsal striatal to ventromedial prefrontal cortical circuitry, which was in turn associated with anhedonia and psychomotor slowing, respectively. Interestingly, our preliminary data suggest that acute administration of the dopamine precursor, levodopa, can reverse these alterations in corticostriatal connectivity in patients with increased inflammation. These findings indicate that inflammation-related decreases in mesolimbic dopamine may cause reduced connectivity within reward-related corticostriatal circuitry leading to symptoms of anhedonia and psychomotor retardation, which are common to a number of psychiatric disorders and are often resistant to treatment with standard therapies. Thus, the proposed research will test the hypotheses that 1) administration of the dopamine precursor levodopa will increase connectivity in reward-related brain regions in depressed patients with high but not low inflammation, and 2) levodopa will decrease symptoms of anhedonia and psychomotor retardation (assessed using objective and clinical measures of motivation and motor speed) in association with increased connectivity within reward- related brain regions. To test these hypotheses, we will use resting state and task-based functional MRI, task- based and clinical assessments of RDoC constructs of positive and negative valence, and a pharmacological challenge strategy using levodopa. The proposed research will establish the role of dopamine in the effects of inflammation on reward circuitry and related behavior. In addition, the proposed studies will elucidate reliable imaging biomarkers that will allow determination of target engagement in the brain of novel therapeutic strategies that modulate dopamine pathways to reverse the effects of inflammation on motivation and motor function in patients with neuropsychiatric disorders including depression.